ITMI20012186A1 - PROCEDURE FOR THE PREPARATION OF 14-BETA-HYDROXY-BACCATIN III-1,14-CARBONATE - Google Patents

Abstract

A process for the preparation of 14beta-hydroxy-baccatin III-1,14-carbonate useful for the preparation of novel taxane derivatives with antitumor activity.

Description

Description of the industrial invention entitled:

"PROCEDURE FOR THE PREPARATION OF 14BETA-HYDROXY-BACCATIN III-1,14-CARBONATE"

The invention described herein refers to the preparation of 14β-hydroxy-1,14-carbonate-baccatine III. The product obtained with the process of the invention can be used in the preparation of new taxane derivatives with antitumor activity.

Taxanes constitute one of the most important classes of anticancer developed in recent years. Paclitaxel is a diterpene complex isolated from the bark of Taxus brevifolia and is considered one of the leading cancer therapy drugs. An extensive research is currently underway for new derivatives with a taxane structure with superior pharmacological activity and improved pharmacokinetic profile. A particular line of research concerns the compounds derived from baccatine III variously modified with respect to the basic structure. Examples of such compounds are represented by the derivatives of 14β-hydroxy baccatine III described in US publications 5705508, WO 97/43291, WO 96/36622. Currently the derivatives of 14 β-hydroxideacetylbaccatin III 1,14-carbonate are prepared starting from the precursor 14-β-hydroxy-deacetylbaccatin III, which is a natural compound obtainable in small quantities by extraction from Taxus wallichiana leaves, as described in EP 559019. The need is strongly felt to have new procedures for the preparation of large quantities of

carbonate-baccatine III which allows you to prepare its derivatives in a simple and effective way.

It has now been found that it is possible to prepare 14β-hydroxy-1,14-carbonatobaccatin III with a synthesis process that uses 13-ketobaccatin III as the starting compound, a compound that can easily be obtained from 10-deacetylbaccatin III which, at unlike 14-β-hydroxybaccatin III, it can be easily and in large quantities isolated from Taxus baccata leaves.

Therefore, the invention provides a process for the preparation of 14β-hydroxy-baccatine III-1,14-carbonate which includes the following steps:

to. treatment of 7-triethylsilyl-13-ketobaccatin III of formula

with bases and suitable oxidants, to give 7-triethylsilyl-13-keto-14-hydroxybaccatin III:

b. carbonation of hydroxyls 1 and 14 to give 7-TES-13-ketobaccatin III-1,14-carbonate:

c. reduction of the ketone in position 13 and removal of the protector in 7.

The starting 13-ketobaccatin III is conveniently protected in position 7 with a suitable protecting group, preferably selected from silyl ethers (especially triethylsilyl ether). Step a) is carried out by treatment with a suitable base, in particular potassium t-butoxide (t-BuOK) or potassium bis (trimethylsilyl) azide (KHMDS). The reaction can be carried out from -40 to -78 ° C. Suitable solvents for this reaction are ethers, such as tetrahydrofuran or diethyl ether, in particular in admixture with HMPA or DMPU. The enolate is then treated with an oxidizing agent, such as oxaziridine derivatives (in particular N-benzenesulfonylphenyl oxaziridine, N-benzenesulfonyl-m-nitrophenyloxaziridine and camphorsulfonyloxaziridine) to provide the derivative of 13-keto-14-hydroxybaccatin III 7-protected.

Step b) is then carried out by treatment with a carbonylating agent (for example carbonyldiimidazole or phosgene) under conditions usually described in the literature, to provide the 1,14-carbonate derivative. The reaction can be conveniently carried out in inert solvents, especially ethers or chlorinated solvents, in the presence of a base (preferably pyridine or triethylamine), at a temperature between -40 ° C and room temperature.

The reaction can be carried out both on the pure starting material and on the raw material coming from the previous stage.

The reduction of the carbonyl in position 13 of stage c is easily carried out with sodium borohydride in ethanol in the temperature range usually -20 to -50 ° C, and is complete within 2 - 6 hours. The reaction can also be carried out in methanol, isopropanol, or in a mixture of methanol and tetrahydro furan. The reducing agent can be used in stoichiometric quantities, although it is preferable to add an excess of hydride. The reduction can also be carried out with other hydrides including, but not limited to, tetrabutylammonium borohydride, lithium borohydride, sodium triacetoxyborohydride under the conditions known in the art.

The removal of the protection in position 7 takes place in the conditions suitable for the group introduced. For example, if the protecting group in position 7 is triethylsilylether, hydrolysis with hydrochloric acid in methanol or hydrofluoric acid and pyridine in acetonitrile can be successfully used.

13-keto-baccatine III can be conveniently obtained by oxidation of baccatine III. The oxidation of baccatine III can also be achieved with ozone but also with manganese dioxide in aprotic solvents such as methylene chloride, tetrahydrofuran, acetone, ethyl acetate. The reaction can be carried out at 0 ° C - 60 ° C, more preferably at room temperature.

The processes of the invention described above are summarized in the following scheme:

The following examples further illustrate the invention.

EXAMPLES

13-Keto-baccatina III

Baccatine III (150 g, 0.25 mol) was dissolved in acetone (1.43 L). Commercially available manganese dioxide (450 g) was added in three portions with vigorous stirring. After disappearance of the starting product (4 h) the suspension was filtered and the solvent evaporated. The crude was suspended in EtOAc (100 mL) and refluxed for 1 h. C-Hex (100 mL) was then added. The title compound was obtained from the mother liquors, after evaporation of the solvent, as a white solid (140 g, 95%).

7-TES-13-keto-baccatine III

13-Keto-baccatine III (5 g, 8.5 mmol), TESC1 (3.6mL, 21.4 mmol, 2.5 eq) and N-methylimidazole (2.73 mL, 34.3 mmol, 4 eq) were dissolved in anhydrous DCM (25 mL). The solution was left under stirring for 1.5h then quenched by slowly pouring it into 2M NaHS04 (25 mL). The aqueous layer was washed, extracted with DCM (2 x 10 mL) and the combined organic layer was extracted with brine (2 x 20 mL). The organic solution was dried over sodium sulfate to give 4.7 g of the title compound, sufficiently pure for the next step.

14-Hydroxy-7-TES- 13-keto-baccatine III

7-TES- 13-keto-baccatine III (670 mg, 0.96 mmol) was dissolved in a mixture of anhydrous THF (9 ml) and DMPU (2 ml) and cooled to -60 ° C below N2. A solution of 1M t-BuOK in THF (2.5 ml, 0.86 mmol), previously cooled to -50 ° C, was dropped into it. This solution was stirred at -60 ° C for 45 minutes, then added dropwise (±) -camphorsulfonyloxaziridine (440 mg, 2 mmol) dissolved in anhydrous THF (2 ml). The reaction mixture was stirred for 3 hours at -60 ° C then quenched with a 10% solution of AcOH in anhydrous THF (2 mL). The mixture was then allowed to warm to room temperature, then extracted with DCM (2 x 10 mL). The combined organic layers were washed with water, a saturated aqueous solution of NaCl (15 ml) and dried over Na2S40. The title compound was purified by flash chromatography (silica gel, cHex-AcOEt, 8: 2) with a yield of 79%. Alternatively it was used directly in the next step without further purification.

1βB-Hydroxy-7-TES-13-keto-baccatine III 1,14-carbonate

A solution of 14β-hydroxy-7-TES-13-keto-baccatine (12.2 g) in anhydrous DCM (50 mL) and pyridine (16 mL) was dropped into a 20% solution of phosgene in DCM (45 mL, 5 eq) at -10 ° C. After 2 hours the reaction was added dropwise to an aqueous solution of 5% NaHC03 (100 mL). The aqueous layer was washed with DCM (3 x 50 mL) and the crude was purified by flash chromatography (silica gel, DCM-AcOEt = 50: 1) to give the title compound with a yield of 95%

14β-Hydroxy-7-TES-baccatine III 1.14-carbonate

A suspension of NaBH4 (0.5 g) in absolute ethanol (10 mL) was cooled to -50 ° C, and a cooled solution of 14-hydroxy-7-TES-13-keto-baccatine III 1.14 - was added to it β-carbonate (0.5 g, 0.6 mmol) in absolute ethanol (10 mL). After disappearance of the starting product (8 h) the reaction was quenched with citric acid and extracted with EtOAc. The combined organic layers were dried over sodium sulfate and the solvent was evaporated. The title compound was obtained as a white solid with a yield of 85%, after chromatography. P.F:

14B-Hydroxy-baccatine III 1.14-carbonate

14-Hydroxy-7-TES-baccatine III 1,14-β-carbonate (9.6 g, 1.3 mmol) was dissolved in a mixture of acetonitrile (5.4 mL) and pyridine (6.4 mL) cooled to 0 ° C. A solution of 70% HF in pyridine (0.95 mL) was dropped in 15 min, the solution was stirred at rt. overnight. The reaction mixture was then poured into 20 mL of ice and left to stir for 1 h. The mixture was then extracted with DCM (3 x 10 mL) and the combined organic layers were washed with 10% NaHS04 (to pH = 2), 5% NaHC03 (2 x 10 mL) and brine (2 x 10 mL ). After evaporation of the solvent, the title compound was obtained as a white solid with a yield of 96%.

Claims (10)

CLAIMS 1. A process for the preparation of 14beta-hydroxy-1,14-carbonatobaccatin III which includes: to. treatment of 7-triethylsilyl-13-ketobaccatin III of formula with bases and suitable oxidants, to give 7-triethylsilyl- 13-keto- 14-hydroxybaccatin III: b. carbonation of hydroxyls 1 and 14 to give 7-TES-13-keto-baccatine III- 1,14-carbonate: c. reduction of the ketone in position 13 and removal of the protector in 7. 2. Process according to claim 1 wherein step a is carried out by treatment with potassium t-butoxide or potassium bis (trimethylsilyl) azide at a temperature from -40 to -78 ° C in ethers mixed with HMPA or DMPU, in the presence of oxaziridine derivatives. 3. A process according to claim 2 wherein the oxaziridine derivative is selected from N-benzenesulfonylphenyl oxaziridine, N-benzenesulfonylm-nitrophenyloxaziridine and camphorsulfonyloxaziridine. 4. A process according to any one of claims 1 to 3, in which step b) is carried out by treatment with a carbonyldiimidazole or phosgene in chlorinated solvents in the presence of a base at a temperature varying between -40 ° C and room temperature. A process according to any one of claims 1 to 4, wherein step c) is carried out by treatment with a hydride at a temperature of -20 to -50 ° C. 6. A process according to claim 5 in which the hydride is selected from sodium borohydride, lithium borohydride, sodium triacetoxyborohydride and the reaction is carried out in ethanol, methanol, isopropanol, or in a mixture of methanol and tetrahydrofuran. 7. Process according to any one of claims 1 to 6 in which the 13-keto-baccatine III protected with hydroxyl in 7 is prepared by selective acetylation of hydroxyl 10 followed by oxidation of hydroxyl 13 and protection of hydroxyl 7. 8. A process according to claim 7 wherein 13-keto-baccatine III is obtained by selective acetylation in 10 of deacetylbaccatin III with acetic anhydride followed by oxidation with manganese dioxide in aprotic solvents at 0 ° C - 60 ° C. 9. As a new intermediate, the compound 7-triethylsilyl-13-keto-14-hydroxybaccatin III, of formula 10. As a new intermediate, the compound 7-TES-13-keto-baccatine III-1,14-carbonate, of formula: